A5005770804- Cancer-related Molecular Pathways
- Prostate Cancer Treatment and Research
- Advanced Breast Cancer Therapies
- Protein Degradation and Inhibitors
- Cancer, Lipids, and Metabolism
- Ubiquitin and proteasome pathways
- Estrogen and related hormone effects
- Poxvirus research and outbreaks
- Bacillus and Francisella bacterial research
- Click Chemistry and Applications
- Genomics and Chromatin Dynamics
- Yersinia bacterium, plague, ectoparasites research
- Cancer Genomics and Diagnostics
- Chronic Lymphocytic Leukemia Research
- HER2/EGFR in Cancer Research
Massachusetts Institute of Technology
2019
United States Army Medical Command
2018
Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay identified KI-ARv-03 as an complex binder that reduces AR-driven proliferation in cancer cells. We deduced be potent, selective inhibitor CDK9, important cofactor for AR, MYC,...
Transcriptional deregulation is a hallmark of many cancers and exemplified by genomic amplifications the MYC family oncogenes, which occur in at least 20% all solid tumors adults. Targeting transcriptional cofactors cyclin-dependent kinase (CDK9) has emerged as therapeutic strategy to interdict deregulated activity including oncogenic MYC. Here, we report structural optimization small molecule microarray hit, prioritizing maintenance CDK9 selectivity while improving on-target potency overall...
Tularemia is a rare but potentially fatal disease that develops in numerous wild and domestic animals, including lagomorphs, rodents, cats, humans. Francisella tularensis bacterium, the causative agent of tularemia, was identified by veterinary personnel at Fort Riley, Kansas during routine post-mortum evaluation feline. However, before formal diagnosis confirmed, sample sent prepared for rabies testing Department Defense (DoD) U.S. Army Public Health Command Central (PHC-C), Food Analysis...
Abstract Tumorigenesis is driven by the accumulation of adverse genetic changes resulting in dysregulated transcription promoting altered gene expression and cancer cell state. Thus, tumors can develop dependencies on transcriptional regulators that promote reprogrammed landscape. One such regulator cyclin-dependent kinase 9 (CDK9), which regulates elongation promotes activation factors. We developed a potent, selective, orally bioavailable CDK9 inhibitor, KB-0742. KB-0742 highly selective...
Abstract KB-0742 is an orally available, potent, and selective inhibitor of cyclin-dependent kinase 9 (CDK9). Sensitivity profiling across a panel 800 adherent suspension immortalized pan-cancer cell lines using the Broad Institute PRISM platform had previously demonstrated MYC amplification as being driver sensitivity. We sought to further determine activity in breast cancer lines, patient-derived organoid cultures, xenograft (PDX) models. decreased viability derived from primary metastatic...
Abstract Transcriptional deregulation is a hallmark of many cancers, including subset that are “transcriptionally addicted” and depend on high levels transcription for oncogenic program genes. Although these tumors thought to be highly susceptible targeting the transcriptional apparatus, their molecular definition remains challenging. To better define sensitivity inhibition, we profiled pan-cancer KB-0742 — potent, selective, orally bioavailable small molecule inhibitor elongation cofactor...
Abstract MYC is the most frequently amplified gene in human cancers and one of sought-after drug targets for cancer therapy. Its function as a transcription factor essential its oncogenic potential. However, development small molecules that target cells has been intractable due to lack known ligand binding sites. To overcome these structural challenges, we leveraged Kronos Bio’s molecule microarray (SMM) screening platform identify can bind transcriptional complexes cell lysates from with...
Abstract The androgen receptor (AR) is a well-established oncogenic driver of prostate cancer, and AR-targeting hormone therapy has proven an efficacious treatment option for patients with metastatic cancer. Due to the importance AR in cancer disease progression, we leveraged small molecule microarray (SMM) screening technology identify compounds that bind transcriptional complexes common splice-variant, AR-V7, present along castration-resistant cell lysates. A subset SMM hits were...
Abstract Castration resistant prostate cancers (CRPCs) lose sensitivity to hormone therapy, but remain dependent on oncogenic transcription programs driven by the androgen receptor (AR) and other factors such as MYC. Using small molecule microarrays (SMMs), we screened HEK293 cellular lysates for compounds binding exogenously expressed ARv7, a mutant splice form of AR that drives castration resistance. Although like ARv7 MYC are considered classically undruggable, SMMs able identify...